Chronic pain from nerve injury is a debilitating condition that affects millions of Americans. Such pain can occur as a result of cancer, multiple sclerosis, HIV-associated neuropathy, diabetic neuropathy, trigeminal neuralgia, postherpetic neuralgia (shingles), phantom limb pain, nerve injury due to trauma or surgery, and deafferentation pain. Most of these chronic pain syndromes are refractory to standard analgesics such as morphine and non-steroidal anti-inflammatory drugs. In addition, such drugs must be given in high doses such that they are associated with a variety of side effects that often limits the long-term use. Many of these side effects are life-threatening such as kidney toxicity and gastrointestinal distress in the case of the non-steroidal anti-inflammatory drugs and respiratory depression in the case of morphine.
In addition to the known toxicities of opioids, morphine, and other opioids used as standards of care for pain treatment, also can be limited in their therapeutic use by the development of hyperalgesia and tolerance. Both of these conditions lead to a failure of opioid therapy to produce pain relief in patients, which can be debilitating. Neuronal plasticity associated with hyperalgesia and morphine tolerance has similar cellular and molecular mechanisms, suggesting predictable interactions between hyperalgesia and morphine tolerance (Mao, J. et al. 1995. Pain 62:259-274; Mayer, D. J. et al. 1999. Proc. Natl. Acad. Sci. USA 96:7731-7736). The induction of pain facilitation by sustained opioid exposure contributes to the development of opioid anti-nociceptive tolerance, and manipulations that block enhanced pain also block anti-nociceptive tolerance (Ossipov, M. H. et al. 2003. Life Sci. 73:783-800). The role of glia and their secretory products, particularly pro-inflammatory cytokines, in the development of morphine tolerance, and morphine-withdrawal-induced hyperalgesia, have been recently studied (Song, P. And Z-Q. Zhao. 2001. Neurosci. Res. 39:281-286; Raghavendra, V. et al. 2002. J. Neurosci. 22:9980-9989). Both glial (microglia and astrocyte) activation and enhanced pro-inflammatory cytokine levels were observed following chronic morphine treatment at the lumbar spinal cord of the rat (Raghavendra, V. et al. 2002. J. Neurosci. 22:9980-9989). Inhibition of astrocyte activation or antagonizing the activity of pro-inflammatory cytokines (interleukin-1β, interleukin-6 and tumor necrosis factor-α) attenuated the development of morphine tolerance, and withdrawal-induced hyperalgesia in rats (Song, P. And Z-Q. Zhao. 2001. Neurosci. Res. 39:281-286; Raghavendra, V. et al. 2002. J. Neurosci. 22:9980-9989; Johnston, I. et al. 2003. J. Pain 4(S1):52).
Propentofylline is a xanthine derivative that has been tested extensively in humans as a neuroprotective agent for treatment of Alzheimer's Disease and vascular dementia. It has a different pharmacological profile than other classical methylxanthines including theophylline and caffeine. In clinical trials, propentofylline has been shown to be both safe and effective for the treatment of these neurodegenerative diseases (Mielke et al., Alzheimer Dis. Assoc. Disord., 1998, 12, S29-35; Rother et al., Dement. Geriatr. Cogn. Disord., 1998, 9, 36-43). The effects observed with propentofylline treatment include a reduction in the extent of brain neuropathology, an improvement in cognitive function, a decrease in activation of microglia, and inhibition of inflammatory processes. The drug is well absorbed and extensively metabolized following oral dosing (Kwon et al., Arch. Pharm. Res., 1998, 21, 698-702). The pharmacokinetic and pharmacodynamic profile of propentofylline have made it a promising therapeutic in the treatment of neurodegenerative diseases.
The pharmacological effects of propentofylline have been linked to inhibition of adenosine transport and inhibition of phosphodiesterase. Studies have also suggested this drug has effects to stimulate the synthesis and secretion of nerve growth factor, and can act as a transcriptional modulator and inducer of apoptosis in certain types of brain cells (Kamada et al., No To Shinkei, 1996, 48, 1022-1028). Propentofylline has also been shown to have a differential effect on the production of certain cytokines such as interleukin-6, interleukin-1 beta, and tumor necrosis factor alpha (Miki et al., Clin. Ther., 1991, 13, 747-753). It is known as well to modulate glial activity under pathological conditions. Propentofylline depresses the activation of microglia and astrocytes, which are associated with neuronal damage during ischemic injury (DeLeo, J. et al. 1988. Neurosci. Lett. 84:307-311; Schubert, P. et al. 1997. Ann. NY Acad. Sci. 826:337-347).
Studies have shown that propentofylline is capable of attenuating nerve injury-induced hyperalgesia in rats (Sweitzer, S. M. et al. 2001. J. Pharmacol. Exp. Ther. 297:1210-1217). Although the specific mechanism of propentofylline-induced effects on hyperalgesia remains unknown, several actions have been proposed. Propentofylline has been shown to inhibit adenosine transport and the cyclic-adenosine-5′,3′-monophosphate (cAMP)-specific phosphodiesterase (PDE IV) leading to the induction of cAMP (Meskini et al. 1994; Nagata et al. 1985; Parkinson and Fredholm 1991). Strengthening of cAMP-dependent signaling decreases microglial proliferation and activation in culture (Si et al. 1996), providing a possible mechanism for propentofylline-induced glial modulation. Glial activation and increased pro-inflammatory cytokines are observed during morphine tolerance and withdrawal-induced hyperalgesia.
Glial cells contribute to synaptic homeostasis by releasing neurotrophic factors, promoting synaptogenesis and preventing glutamate excitotoxicity by promoting Na+-dependent glutamate uptake (Liberto et al. 2004). To date, five glutamate transporter subtypes have been identified (Danbolt 2001). EAAT1/GLAST and EAAT2/GLT-1 are thought to be primarily localized to astrocytes although they have recently been demonstrated to be expressed on (Lopez-Redondo et al. 2000) and neurons (Chen et al. 2004). In vitro, activated astrocytes have been shown to express low levels of GLT-1 which are enhanced upon dibutyryl-cAMP (db-cAMP) stimulation-induced differentiation (Schlag et al. 1998). Activated astrocytes may lose their homeostatic functions upon exposure to stressors and increase the expression of cytokines, nitric oxide and prostaglandins as an injury response (Watkins et al. 2001). Prior studies have determined that 7 days post-chronic constriction injury (Sung et al. 2003), or facial nerve axotomy (Lopez-Redondo et al. 2000), glial glutamate transporters are decreased corresponding temporally to our observation of enhanced astrocytic activation (Sweitzer et al. 2001; Tanga et al. 2004).
It has now been found that propentofylline, a drug shown to have a favorable safety profile in humans with neurodegenerative disease, has the ability to attenuate the development of hyperalgesia and the expression of analgesic tolerance to opioids, such as morphine.